eLife Assessment

This fundamental work extends our understanding of the role of TGFβ2 as a modulator of mechanosensing in the eye and identifies the TRPV4 ion channel as a common regulator of Trabecular Meshwork (TM) contractility and pathological OHT and the data and evidence provided are convincing. This work will clearly be of interest to researchers investigating the role of mechanosensors in the TM and may underpin future research into treatments that aim to lower intra ocular pressure. This work will additionally be of interest to the growing field of researchers investigating the regulation of force sensing via ion channels and their roles in health and disease, in particular the ion channel TRPV4.

eLife Assessment

This important study presents a pipeline for discovering cooperative transcription factor (TF) interactions that regulate development, and applies this pipeline in a systematic investigation of TF co-regulation in 11 human embryonic tissues. The authors provide overall solid bioinformatics and experimental support for their findings: although they make a convincing argument for the role of TEAD factors as co-repressors of regulatory activity with tissue-specific TFs, other aspects of the study would benefit from additional validation. This work would be of interest to cell biologists focused on development or on discovery of TF relationships.

eLife Assessment

There is a growing interest in understanding the individuality of animal behaviours. In this article, the authors build and use an impressive array of high throughput phenotyping paradigms to examine the 'stability' (consistency) of behavioural characteristics in a range of contexts and over time. They find that certain behaviours are individualistic and persist robustly across external stimuli while others are less robust to these changing parameters. The data, while extensive are incompletely analysed/explained. With more appropriate statistical methods adopted, the findings would have important implications for the study of individual variability.

eLife Assessment

This important study tests the development of motor reinforcement learning from toddlerhood to adulthood, using a large online sample. They show that learning improves with age in a task that, like real-life movement, involves a continuous range of response options and probabilistic rewards, and link this shift to reduced movement variability and more efficient feedback-based learning through behavioural modeling. Simplifying the task with discrete actions and deterministic outcomes boosted younger children's performance, suggesting early learning is limited by spatial and probabilistic processing. The evidence is convincing, although future work may investigate more naturalistic movement.

eLife Assessment

This study provides an important set of analyses and theoretical derivations to understand the mechanisms used by recurrent neural networks (RNNs) to perform context-dependent accumulation of evidence. The results regarding the dimensionality and neural dynamical signatures of RNNs are convincing and provide new avenues to study the mechanisms underlying context-dependent computations. This manuscript will be of interest to a broad audience in systems and computational neuroscience.

eLife Assessment

The manuscript contains important findings regarding inflammatory macrophage subsets that have theoretical and/or practical applications beyond the field of rheumatology. The authors demonstrate with compelling evidence the effects of PGE2 on TNF signaling. This work will be of broad interest to immunologists and cell biologists.

eLife Assessment

The authors study the context of the skeletal remains of three individuals and associated sediment samples to conclude that the hominin species Homo naledi intentionally buried their dead. Demonstration of the earliest known instance of intentional funerary practice – with a relatively small-brained hominin engaging in a highly complex behavior that has otherwise been observed from Homo sapiens and Homo neanderthalensis – would represent a landmark finding. The authors have revised their manuscript extensively in light of the reviews of their initial submission, with improved illustration, context, discussion, and theoretical frameworks, leading to an improved case supporting their conclusion that Homo naledi intentionally buried their dead. One of the reviewers concludes that the findings convincingly demonstrate intentional burial practices, while another considers evidence for such an unambiguous conclusion to be incomplete given a lack of definitive knowledge around how the hominins got into the chamber. We look forward to seeing the continued development and assessment of this hypothesis. It is worth noting that the detailed reviews (both rounds) and comprehensive author response are commendable and consequential parts of the scientific record of this study. The editors note that the authors' response repeatedly invokes precedent from previous publications to help justify the conclusions in this paper. While doing so is helpful, the editors also note that scientific norms and knowledge are constantly evolving, and that any study has to rest on its own scientific merit.

eLife Assessment

The songbird vocal motor nucleus HVC contains cells that project to the basal ganglia, the auditory system, or to downstream vocal motor structures. In this fundamental study, the authors conduct optogenetic circuit mapping to clarify how four distinct inputs to HVC act on these distinct HVC cell types. They provide compelling evidence that all long range projections engage inhibitory circuits in HVC and can also exhibit cell-type specific preferences in monosynaptic input strength. Understanding HVC at this microcircuit level is critical for constraining models of song learning and production.

eLife Assessment

The study reports valuable findings from a very rich EEG-fMRI dataset, including 107 participants, which was collected during nocturnal naps. Using overall solid methods, the authors link activity in memory-related brain regions (e.g., hippocampus, thalamus, and medial prefrontal cortex), and their functional connectivity to the occurrence of canonical sleep rhythms (spindles and slow oscillations) in non-rapid eye movement sleep. This work will be of broad interest to sleep and memory researchers and beyond.

eLife Assessment

The findings of this study are valuable, offering insights into the neural representation of reversal probability in decision-making tasks, with potential implications for understanding flexible behavior in changing environments. The study contains interesting comparisons between neural data and models, including evidence for partial consistency with line attractor models in this probabilistic reversal learning task. However, it remains incomplete due to issues related to how the RNN training and the analysis of its dynamics, which renders the evidence as not complete.

eLife Assessment

This valuable paper uses a quantitative modeling approach to explore a well-studied transition in motor behavior in the nematode C. elegans. The authors provide solid evidence that this transition, which has been considered by many in the field to be a two-state behavior, can instead be described as a process whose parameters are smoothly modulated within a single state. This finding provides insight into the relationships between latent internal states and observable behavioral states, and suggests that relatively simple neuronal mechanisms can drive behavioral sequences that appear more complex.

eLife Assessment

This study provides valuable insights into the evolutionary conservation of sex determination mechanisms in ants by identifying a candidate sex-determining region in a parthenogenetic species. The strength of evidence is solid, using genomic analyses to identify differences in heterozygosity between females and diploid males, though the conclusions are limited by the lack of functional analysis.

eLife Assessment

This manuscript presents an interesting new framework (VARX) for simultaneously quantifying effective connectivity in brain activity during sensory stimulation and how that brain activity is being driven by that sensory stimulation. The reviewers thought the model was original and its conclusion that intrinsic connectivity is reduced (rather than increased) during sensory stimulation is very interesting, but that for ideal performance, one must specify all sensory features in the model, which is not possible. Overall, however, this work is important with convincing evidence for its conclusions - it will be of interest to neuroscientists working on brain connectivity and dynamics.

eLife Assessment

This valuable work presents an interpretable protein-DNA Energy Associative (IDEA) model for predicting binding sites and affinities of DNA-binding proteins. While the method is convincing, it requires some adaptation for application to different proteins. The IDEA method is available and can be potentially used for predicting genome-wide protein-DNA binding sites.

eLife Assessment

In this important paper, the authors use single-cell RNA sequencing to understand post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastoma genesis. The authors report findings that have practical implications for retinal development, gene expression, and cell fate specification. The evidence is compelling as the experimental design and analysis are exceptionally rigorous.

eLife Assessment

This useful manuscript addresses a stability issue for long-term chronically implanted array recordings and electrolytic lesioning, which is relevant to both basic science and translational research. The authors provide a systematic scanning electron microscopy (SEM) of explanted arrays, evaluating electrode damage and sharing extensive datasets accessible through interactive plots. The strength of the evidence is solid, but it can be improved by performing additional analyses on complementary neurophysiology, functional, or histological data.

eLife Assessment

This fundamental study demonstrates how a left-right bias in the relationship between numerical magnitude and space depends on brain lateralization. The evidence is compelling, and the manuscript could be strengthened by improving its contextualization, presentation, and discussion. The results will be of interest to researchers studying numerical cognition, brain lateralization, and cognitive brain development more broadly.

eLife Assessment

This manuscript develops a theoretical model of osmotic pressure adaptation in microbes by osmolyte production and wall synthesis. The prediction of a rapid increase in growth rate on osmotic shock is experimentally validated using fission yeast. By using phenomenological rules rather than detailed molecular mechanisms, the model can potentially apply to a wide range of microbes, providing important insights that would be of interest to the wider community studying the regulation of cell size and mechanics. The level of coarse-graining and the assumptions and limitations of the model have been well described, providing a convincing foundation for making predictions. However, further experimental work on the validity of the core assumptions across a range of microbial organisms is needed to assess the universality of the model.

eLife Assessment

This paper presents important information about potential Homo naledi-associated markings discovered on the walls of the Hill Antechamber of the Rising Star Cave system, South Africa. If confirmed, the antiquity, intentionality, and authorship of the reported markings will have profound archaeological implications, as such behaviors are otherwise widely considered to be unique to our species, Homo sapiens. This report concerns preliminary findings and as it stands the study is incomplete, with further work needed in the future to support the claims about the anthropogenic nature, age, and author of the engravings.

eLife Assessment

This important study uses Mendelian Randomization to provide evidence that early-life reproductive phenotypes (i.e., age at onset of menarche and age at first birth) have a significant impact on numerous health outcomes later in life. The empirical evidence provided by the authors supporting the antagonistic pleiotropy theory is solid. Theories of aging should be empirically tested and this study provides a good first step in that direction.

eLife Assessment

This study on the effect of the trophic factor BDNF upon dental cells is an understudied subject that is relevant to dental regeneration and repair. Given that the topic is new and has not been covered previously, the report is a useful foray into a new area of investigation, although several experimental results could be strengthened. The connection of BDNF and dental health is a solid attempt in potentially translating trophic factor signaling clinically, which has been stymied in past efforts.

eLife Assessment

A combination of molecular dynamics simulation and state-of-the-art statistical post-processing techniques provided valuable insight into GPCR-ligand dynamics. This manuscript provides solid evidence for differences in the binding/unbinding of classical cannabinoid drugs from new psychoactive substances. The results could aid in mitigating the public health threat these drugs pose.

eLife Assessment

This fundamental study investigates the role of polyunsaturated fatty acids (PUFAs) in physiology and membrane biology, using a unique model to perform a thorough genetic screen that demonstrates that PUFA synthesis defects cannot be compensated for by mutations in other pathways. These findings are supported by compelling evidence from a high quality genetic screen, functional validation of their hits, and lipid analyses. This study will appeal to researchers in membrane biology, lipid metabolism, and C. elegans genetics.

eLife Assessment

This paper provides a useful new theory of the hallucinatory effects of psychedelics. The authors present convincing evidence that a computational model trained with the Wake-Sleep algorithm can reproduce some features of hallucinations by varying the strength of top-down connections in the model, but discussion of the model's relationships to the psychedelics and sleep literatures is incomplete. The work will be of interest to researchers studying hallucinations or offline activity and learning more broadly.

eLife Assessment

This study proposes a potentially useful improvement on a popular fMRI method for quantifying representational similarity in brain measurements by focusing on representational strength at the single trial level and adding linear mixed effects modeling for group-level inference. The manuscript demonstrates increased sensitivity with no loss of precision compared to more classic versions of the method. However, the framing of the work with respect to these prior approaches is incomplete, several assumptions are insufficiently motivated, and it is unclear to what extent the approach would generalize to other paradigms.

eLife Assessment

In this valuable study, Wandler et al. provide convincing theoretical evidence for alternate mechanisms of rhythm generation by CPGs. Their model shows that cell-type-specific connectivity and a dominant inhibitory drive could underlie rhythm generation. Excitatory input could act to enhance the frequency range of these rhythms. This modeling study could motivate further experimental investigation of these mechanisms to understand CPG rhythmogenesis.

eLife Assessment

This important work compares the size of two brain areas, the amygdala and the hippocampus, across 12 species belonging to the Macaca genus. The authors find, using a convincing methodological approach, that amygdala - but not hippocampal - volume varies with social tolerance grade, with high tolerance species showing larger amygdala than low tolerance species of macaques. Interestingly, their findings also suggest an inverted developmental effect, with intolerant species showing an increase in amygdala volume across the lifespan, compared to tolerant species exhibiting the opposite trend. Overall, this paper offers new insights into the neural basis of social and emotional processing.

eLife Assessment

This is a useful tool for code-less analysis of patterns in cell migratory behaviours in vivo using intravital microscopy data and allows correlation with spatial features of the tumour microenvironment. There is a need for these tools to make quantitative analysis, comparison and interpretation of complex cell tracking data more accessible and evidence is provided of its applicability to tracks generated by both proprietary and open tracking software. However, it is incomplete due to limitations imposed by the assumptions that apply to the statistical tests employed.

eLife Assessment

This important study investigates the role of Drp1 in early embryo development. The authors have addressed most of the original comments and the work now presents convincing evidence on how this protein influences mitochondrial localization and partitioning during the first embryonic divisions. The research employs the Trim-Away technique to eliminate Drp1 in zygotes, revealing critical insights into mitochondrial clustering, spindle formation, and embryonic development.

eLife Assessment

This valuable study provides a novel framework for leveraging longitudinal field observations to examine the effects of aging on stone tool use behaviour in wild chimpanzees. The methods and results are robust providing solid evidence of the effects of old age on nut cracking behaviour at this field site. Despite the low sample size of five individuals, this study is of broad interest to ethologists, primatologists, archaeologists, and psychologists.

eLife Assessment

This important study explores the mechanisms underlying the maintenance of cell surface protein levels. The authors present solid evidence to support their claims, though the addition of certain validation experiments could have further strengthened the conclusions. This work will be of particular interest to cell biologists focused on membrane trafficking.

eLife Assessment

This valuable study uses AlphaFold2 to guide the structural modelling of different states of the human voltage-gated potassium channel KV11.1, a key pharmacological drug target. Follow-up molecular dynamics and drug-docking simulations, combined with experimental characterization, offer convincing evidence supporting the models. The work shows potential for improving drug potency predictions in ion channel pharmacology.

eLife Assessment

In this important manuscript, the authors reveal novel findings on the role of exosomes in regulating filopodia formation. Filopodia are crucial for various cellular processes, including migration, polarization, directional sensing, and the formation of neuronal synapses. The authors convincingly demonstrate that exosomes, particularly those enriched with the protein THSD7A, play a significant role in promoting filopodia formation in both cancer cells and neurons.

eLife Assessment

Building on previous structural studies, this work provides valuable new insights into the architecture of the autophagy initiation complex, comprising ULK1, ATG13, and FIP200. The authors present their findings with solid supporting evidence, making this study a significant contribution to the autophagy field.

eLife Assessment

This important study investigates how hummingbird hawkmoths integrate stimuli from across their visual field to guide flight behavior. Cue conflict experiments provide solid evidence for an integration hierarchy within the visual field: hawkmoths prioritize the avoidance of dorsal visual stimuli, potentially to avoid crashing into foliage, while they use ventrolateral optic flow to guide flight control. The paper will be of broad interest to enthusiasts of visual neuroscience and flight behavior.

eLife Assessment

Using a unique cerebellar disruption approach in non-human primates, this study provides valuable new insight into how cerebellar inputs to the motor cortex contribute to reaching. The findings convincingly demonstrate that reaching movements following cerebellar disruption slow down because of both an acute deficit in producing muscle activity as well as a progressive decline in compensating for limb dynamics. This work will be of interest to neuroscientists and clinicians interested in cerebellar function and pathology.

eLife Assessment

The work presents a valuable extension of qFit-ligand, a computational method for modeling conformational heterogeneity of ligands in X-ray crystallography and cryo-EM density maps. The authors provide solid evidence of improved capabilities through careful validation against the previous version, particularly in expanding ligand sampling within conformational space. Such improvements suggest practical utility for challenging applications, including macrocyclic compound modeling and crystallographic drug fragment screening.

eLife Assessment

This important study reports a reanalysis of one experiment of a previously-published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. This paper presents solid evidence that working memory representations are dynamic and distinct from sensory representations of intervening distractions. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife Assessment

In this important study, the authors have performed a zebrafish drug screen to identify suppressors of atherogenic lipoproteins. They utilize a well-established LipoGlo assay to find molecules that modulate these lipoproteins, identifying 49 potential hits. They perform some validation experiments, including studies linking enoxolone to its likely inhibitory effect on a specific transcription factor, HNF4alpha. Overall, the results are convincing and robust, and will open up new areas of exploration for those investigators interested in in vivo lipid biology.

eLife Assessment

This study provides useful information on the impact of Lamin A/C knockdown on gene expression using RNA-Seq analysis. In addition, the impact of Lamin A/C knockdown on telomere dynamics is explored using live cell imaging. The conclusions, however, are inadequately supported by the data presented. Weaknesses include excessive reliance on gene ontology analysis without further validation of direct versus indirect effects, use of only one shRNA, which may have off target effects, validation of knockdown only from gene expression rather than protein levels, lack of discussion on previous studies showing the presence of Lamin A/C in the nuclear interior among others.

eLife Assessment

This study reveals that PRMT1 overexpression drives tumorigenesis of acute megakaryocytic leukemia (AMKL) and that targeting PRMT1 is a viable approach for treating AMKL. After revision, both reviewers found that these findings are important and that the data supporting these findings are convincing. Furthermore, these findings likely have significant implications for the treatment of AMKL with PRMT1 overexpression in the future.

eLife Assessment

This study presents valuable findings on the regulation of survival and maintenance of brain-resident immune cells called microglia. Using compelling and sophisticated genetic tools, the authors demonstrate a gene dosage-dependent mechanism using which microglia are eliminated. This research on cell competition and survival will be of broad interest to the cell biology community.

eLife Assessment

This fundamental work has the potential to advance our understanding of brain activity using electrophysiological data, by proposing a completely new approach to reconstructing EEG data that challenges the assumptions typically made in the solutions to Maxwell’s equations. Convincing evidence for the superior spatio-temporal resolution of this method is provided through a number of experiments, including simultaneous FMRI/EEG acquisitions. This work will be of broad interest to neuroscientists and neuroimaging.

eLife Assessment

The authors investigated the mechanisms underlying the pause in striatal cholinergic interneurons (SCINs) induced by thalamic input, identifying that Kv1 channels play a key role in this burst-dependent pause. The experimental evidence is convincing.<br /> The study provides important mechanistic insights into how burst activity in SCINs leads to a subsequent pause, highlighting the involvement of D1/D5 receptors.

eLife Assessment

This timely and important study used functional near-infrared spectroscopy hyperscanning to examine the neural correlates of how group identification influences collective behavior. The work provides solid evidence to indicate that the synchronization of brain activity between different people underlies collective performance and that changes in brain activity patterns within individuals may, in turn, underlie this between-person synchrony, although the order in which different task stages were completed could not be counter-balanced. This study will be of interest to researchers investigating the neuroscience of social behaviour.

eLife Assessment

This manuscript presents a clever and powerful approach to examining differential roles of Nav1.2 and Nav1.6 channels in excitability of neocortical pyramidal neurons, by engineering mice in which a sulfonamide inhibitor of both channels has reduced affinity for one or the other channels. Overall, the results in the manuscript are compelling and give important information about differential roles of Nav1.6 and Nav1.2 channels. Activity-dependent inactivation of NaV1.6 was also found to attenuate seizure-like activity in cells, demonstrating the promise of activity-dependent NaV1.6-specific pharmacotherapy for epilepsy.

eLife Assessment

This study presents a valuable investigation into how heavy metal stress may have influenced the domestication of maize from its wild ancestor, teosinte parviglumis, focusing on specific ATPase genes with proposed roles in heavy metal homeostasis. The evidence supporting the main claims is incomplete, with suggestive but not definitive data linking gene function to domestication traits, and limited environmental context for the hypothesized selection pressures. While the work introduces an interesting model connecting environmental stress responses to evolutionary transitions and highlights underexplored aspects of teosinte plasticity, the conclusions would benefit from more comprehensive analyses such as transcriptomics, a broader survey of loci, and stronger paleoenvironmental validation. The study will be of interest to researchers in plant evolution and domestication, but currently lacks the analytical depth to fully support its central hypothesis.

eLife Assessment

This study presents valuable findings about daily rhythm changes of the Drosophila melanogaster adult gut metabolome, which is shown to be dependent on the circadian clock genotype, dietary regime and composition, and gut microbiota. The phenomena observed are supported by convincing experimental evidence. The general descriptive approach limits the power of the proposed conclusions. The work will be of interest to a broad range of physiology specialists

eLife Assessment

This study introduces a novel and broadly applicable metric-phenological lag-to partition the effects of spring warming from other abiotic constraints on plant phenology. While the dataset is extensive and the analytical framework is valuable conceptually, the manuscript lacks clarity in its aims and justification for the new metric, and key results are underdeveloped or poorly visualized. The strength of evidence is moderate to solid, but revisions are needed to clarify the study's contribution and improve interpretability.

eLife Assessment

This is a potentially important study that explores the relevant range of parameter values for calibration and validation of cardiac electromechanics in ventricular models. Although much of the work presented is solid, the evidence provided to support the authors' key scientific claims is incomplete, especially as it relates to the emphasis on standardized validation and verification approaches. Notably, the level of model personalization presented in this work falls short of the threshold for what could reasonably be called a "digital twin", even by the relatively relaxed standards that have emerged in computational physiology and related fields in recent years.

eLife Assessment

This study presents significant and novel insights into the roles of zinc in mammalian meiosis/fertilization events. These findings are useful to our understanding of these processes. The evidence presented is solid, with experiments being well-designed, carefully described, and interpreted with appropriate rigor.

eLife Assessment

Inspired by bee's visual behavior, the goal of the manuscript is to develop a model of visual scanning, visual processing and learning to recognize visual patterns. In this model, pre-training with natural images leads to the formation of spatiotemporal receptive fields that can support associative learning. Due to an incomplete test of the necessity and sufficiency of the features included in the model, it cannot be concluded that the model is either the "minimal circuit" or the most biologically plausible circuit of this system. With a more in-depth analysis, the work has the potential of being important and very valuable to both experimental and computational neurobiologists.

eLife Assessment

In their valuable study, Bracey et al. investigate how microtubule organization within pancreatic islet beta cells supports optimal insulin secretion. Using a combination of live imaging and photo-kinetic assays in an in vitro culture system, they provide compelling evidence that kinesin-1-mediated microtubule sliding, which plays critical roles in neurons and embryos, also plays a critical role in forming the sub-membranous microtubule band in response to glucose in beta cells. This work will be of interest to cell biologists studying cytoskeletal dynamics and organelle trafficking, as well as to translational biologists focused on diabetes.

eLife Assessment

This fundamental study provides new insights into the maturation of ribbon synapses in zebrafish neuromast hair cells. Live-cell imaging and pharmacological and genetic manipulations together provide compelling evidence that the formation of this synaptic organelle is a dynamic process involving the fusion of presynaptic elements and microtubule transport, though the evidence that ribbon precursors move in a directed motion toward the active zone is less persuasive. These findings will be of interest to neuroscientists studying synapse formation and function and should inspire further research into the molecular basis for synaptic ribbon maturation.

eLife Assessment

This useful manuscript describes cryo-EM structures of archaeal proteasomes that reveal insights into how occupancy of binding pockets on the 20S protease regulates proteasome gating. The evidence supporting these claims is convincing, although inclusion of more quantitative comparisons would help strengthen the conclusions. This work will be of special interest to researchers interested in proteasome structure and regulation.

eLife Assessment

The findings in this manuscript are fundamental because they identify an entry receptor MYL3 that belongs to the myosin family as a possible target that could inhibit a virus that has a high impact on aquaculture. The evidence is convincing as it contains strong in vitro and in vivo data that support their conclusions; however, studies on the presence of MYL3 in NNV target tissues will further strengthen their claims

eLife Assessment

This valuable study provides in-vivo evidence that CCR4 regulates the early inflammatory response during atherosclerotic plaque formation. The authors propose that altered T-cell response plays a role in this process, shedding light on mechanisms that may be of interest to medical biologists, biochemists, cell biologists, and immunologists. The work is currently considered incomplete pending textual changes and the inclusion of proper controls.

eLife Assessment

This study presents a new, fundamental finding to the field interested in recurrent processing and its neuromodulatory underpinnings, finding unexpectedly that memantine (blocking NMDA-receptors) enhances the decoding of features thought to rely on NMDA-receptors. This interesting, compelling result identifies new directions for researchers studying consciousness, sensory processing, attention, and neurotransmitters.

eLife Assessment

This is a fundamental cell biological study of host responses during symbiotic microbial infection of plants. Compelling imaging-based approaches using genetically encoded cell cycle markers show that in Medicago truncatula root cortex cells, early rhizobial infection events are associated with cell-cycle re-entry, but once the infection is established, host cells exit the cell cycle. The work will be of interest to a wide range of readers working in fields from development and cell biology to plant-microbe interactions.

eLife Assessment

In this convincing work by Yamaguchi et al. the cryo-EM structure of the heterohexameric 3:3 LGI1-ADAM22 complex is presented. The findings suggest that LGI1 can cluster ADAM22 in a trimeric fashion. The clustering of cell surface proteins is important in controlling signaling in the nervous system. This new version of the manuscript has been improved substantially and the figures have been enhanced and clarified.

eLife Assessment

This solid study assesses a mitochondrial polymerase inhibitor in combination with the BCL-2 inhibitor venetoclax, with the aim to increase the elimination of acute myeloid leukemia. It provides valuable findings of combinatorial efficacy using preclinical models in vitro and in vivo, confirming the overall importance of targeting oxidative phosphorylation to overcome venetoclax resistance in acute myeloid leukemia, and could be strengthened through mechanistic studies demonstrating on target effects and pharmacodynamic efficacy in vivo. The study is of interest to hematologists because it addresses a key biomedical issue in acute myeloid leukemia (venetoclax resistance) and provides data regarding the safety and activity of a novel inhibitor of the mitochondrial polymerase in combination with venetoclax.

eLife Assessment

The study presents extensive gene expression profiling and bioinformatic analyses, offering insights into the roles of fibroblasts in cardiac development. The large volume of scRNA-seq data is both compelling and important to the scientific community. All three reviewers agree that the revised manuscript represents a significant improvement and addresses most, if not all, of their previous concerns. The reviewers also acknowledge that detailed mechanistic studies on how fibroblast-derived collagen regulates myocardial and coronary vasculature development are beyond the scope of the current study.

eLife Assessment

This work demonstrates the therapeutic potential of recombinant human PDGF-AB/BB proteins in alleviating the senescent signatures of primary human intervertebral disc cells. The study represents a fundamental, significant advance in the treatment of intervertebral disc degeneration through the suppression of senescence. The strength of evidence supporting these conclusions is compelling, as it is primarily based on transcriptomic analysis and direct protein measurements from relatively homogeneous cell populations. This work will be of interest to spine basic scientists and clinicians, as well as to musculoskeletal scientists more broadly. The revised manuscript adds greater clarity, and the impact of the study is greatly enhanced.

eLife Assessment

This study presents important new insights linking obesity to kidney disease using a Drosophila model. A series of compelling experiments demonstrate that a high-fat diet induces excretion of a leptin-like JAK-STAT ligand from fat body, driving the adipose-nephrocyte axis through activated JAK-STAT signaling and subsequently causing a functional defect in nephrocytes. The approach using combination of genetic tools and pharmacological intervention is solid and confirms the mechanistic link, together with phenotypic analysis that further supports the authors conclusions.

eLife Assessment

Using microscopy experiments and theoretical modelling, the authors present convincing evidence of cellular coordination in the gliding filamentous cyanobacterium Fluctiforma draycotensis. The results are fundamental for the understanding of cyanobacterial motility and the underlying molecular and mechanical pathways of cellular coordination.

eLife Assessment

This fundamental work by Yamamoto and colleagues advances our understanding of how positional information is coordinated between axes during limb outgrowth and patterning. They provide solid evidence that the dorsal-ventral axis feeds into anterior-posterior signaling, and identify the responsible molecules by combining transplantations with molecular manipulations. This work will be of broad interest to regeneration, tissue engineering, and evolutionary biologists.

eLife Assessment

This valuable study investigates how stochastic and deterministic factors are integrated during cellular decision-making, particularly in situations where cells differentiate into distinct fates despite being exposed to the same environmental conditions. The authors present convincing evidence that gene expression variability contributes to the robustness of cell fate decisions in D. discoideum, which sheds light into the role of stochasticity during cell differentiation.

eLife Assessment

The manuscript explores how bacterial evolution in the presence of lytic phages modulates b-lactams resistance and virulence properties in methicillin-resistant Staphylococcus aureus (MRSA). This important work improves our knowledge of how mutation in genes required for phage infection confers sensitivity to b-lactams and alter virulence properties. Altogether, the findings are convincing.

eLife Assessment

The manuscript explores how bacterial evolution in the presence of lytic phages modulates b-lactams resistance and virulence properties in methicillin-resistant Staphylococcus aureus (MRSA). The work is valuable as it identifies underlying mutations that may confer sensitivity to b-lactams and alter virulence properties. While the findings are generally convincing, additional experiments linking how particular mutations regulate phenotypic changes are required to improve the work mechanistically.

eLife Assessment

The study by Power and colleagues is important, as elucidating the dynamic immune responses to photoreceptor damage in vivo potentiates future work in the field to better understand the disease process. The evidence supporting the authors' claims is compelling.

eLife Assessment

This study shows that a peptide called galanin can decrease or increase seizure activity in experimental models of seizures depending on the model. The authors use zebrafish and several methods to address the effects of galanin. The study will be useful to researchers who use zebrafish as experimental animals and who are interested in how peptides like galanin regulate seizures. However, the strength of evidence was considered incomplete at the present time due to several limitations of the results.

Editors Assessment:

This Data Release paper presents the first genome assembly of the lemon sole (Microstomus kitt), a commercially important flatfish found in European coastal waters. It is also interesting that this work was carried out in a University course setting involving the students. The resulting chromosome-level genome was assembled using long-read PacBio HiFi sequencing and the Hi-C technique. The 628 Mbp reference (which is consistent with other Pleuronectidae fish species) is assembled into 24 chromosome-length scaffolds with high completeness, achieving a scaffold N50 of 27.2 Mbp. Peer review and data curation made the author clarify a few points and share all of the data and results in an open and well curated manner. The annotated genome of the lemon sole, with its high continuity, should therefore provide important reference data for future population genetic analyses and conservation strategies of this organism.

This evaluation refers to version 1 of the preprint

eLife Assessment

This fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. After major revisions, the evidence supporting the conclusions is solid. However, some new experiments are needed to draw more robust conclusions regarding the ferroptosis-associated studies.

eLife Assessment

This manuscript describes an important finding of the transcriptional control of a chimeric gene transfer agents (GTA) cluster in Bartonella by a processive anti-termination factor (BrrG). The evidence provided is convincing. This manuscript will interest researchers working on transcriptional regulation, horizontal gene transfer, and phages.

eLife Assessment

This valuable study presents findings on the role of the small GTPase Rab3A in homeostatic plasticity. While the study provides solid evidence for a requirement of Rab3A in homeostatic up-scaling in cultured mouse neurons, it does not provide a model of how Rab3A is involved in homeostatic plasticity. The work will be of interest to researchers in the field of synaptic transmission and synaptic plasticity.

eLife Assessment

This valuable work uses serial block face electron microscopy to reconstruct detailed morphologies of large populations of Drosophila sensory neurons to determine the degree of diversity both within and across distinct neuronal populations. The authors convincingly show that there is considerable morphological diversity even within classes, and develop testable hypotheses about how arbors are optimized for particular sensory function and physiology. This work will be of interest to biologists working in physiology, insect chemosensation, and neuroscience.

eLife Assessment

This manuscript makes a valuable contribution to the field by uncovering a molecular mechanism for miRNA intracellular retention, mediated by the interaction of PCBP2, SYNCRIP, and specific miRNA motifs. The findings are convincing and advance our understanding of RNA-binding protein-mediated miRNA sorting, providing deeper insights into miRNA dynamics.

eLife assessment

This valuable study examines the role of E2 ubiquitin enzyme, Uev1a in tissue resistance to oncogenic RasV12 in Drosophila melanogaster polyploid germline cells and human cancer cell lines. The incomplete evidence suggests that Uev1a works with the E3 ligase APC/C to degrade Cyclin A, and the strength of evidence could be increased by addressing the expression of CycA in the ovaries and the uev1a loss of function in human cancer cells. This work would be of interest to researchers in germline biology and cancer.

eLife Assessment

This study presents a useful finding on the effects of arginine vasopressin (AVP) on islet cells in pancreatic tissue slices, using technically sophisticated spatio-temporal calcium recordings to confirm that AVP influences α and β cells differently depending on glucose concentrations. While the study’s methods – particularly the calcium imaging techniques and peptide ligand design targeting V1b receptors – are strong, the reviewers were concerned about several aspects of the experimental design. The results on β-cell responses are incomplete and insufficient to support the manuscript’s claims, especially due to the high variability of islet responses and lack of mechanistic and functional (hormone release) data. There are also concerns about the possibility of off-target effects and suboptimal receptor specificity: the study would be significantly strengthened by inclusion of signaling pathway interrogation, hormone output assays, genetic validation (e.g., β cell-specific deletion of V1br), and receptor localization. The work will still be of interest to researchers studying islet physiology in the context of health and diabetes.

eLife Assessment

The authors present a computational pipeline for the identification of endogenous allosteric modulators of GPCRs, with experimental validation performed in a yeast system. This approach is valuable for a broad audience, including GPCR structural biologists, molecular pharmacologists, and computational biophysicists. However, the rigor of the computational methods needs to be strengthened to provide stronger evidence for the study's conclusions, which is currently incomplete. The authors should justify their methodological choices and provide greater detail and clarity regarding each computational layer of the pipeline.

eLife Assessment

This valuable study addresses the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau pathology in Caenorhabditis elegans and human cell culture models. The methods are solid and the proposed mechanisms are conceivable. However, the current evidence is incomplete and could be strengthened, due to reliance on imaging data and insufficient biochemical validation. The work will be of broad interest to cell biologists and biologists working on Alzheimer's disease and related proteinopathies.

eLife Assessment

Using advanced CryoEM and mass spectrometry, the authors provide compelling evidence of how tubule formation occurs in an oxygen-dependent manner. These fundamental findings offer a novel mechanism by which rubrerythrin tubules encapsulate encapsulin to prevent oxidative stress in Pyrococcus furiosus. However, there are a few reasonable concerns about biochemical validations and the lack of adequate description of results and methodology.

eLife Assessment

This study presents compelling evidence that the denitrosylase SCoR2 regulates cardioprotective metabolic reprogramming in the heart following ischemia/reperfusion injury. The findings are supported by a novel multi-omics approach and the integration of mouse and human data, which provides valuable insights into S-nitrosylation and cardiac metabolism. However, some conclusions remain limited by unresolved methodological issues that warrant clarification.

eLife Assessment

This important study advances our understanding of population-level immune responses to influenza in both children and adults. The strength of the evidence supporting the conclusions is compelling, with high-throughput profiling assays and mathematical modeling. The work will be of interest to immunologists, virologists, vaccine developers, and those working on mathematical modeling of infectious diseases.

eLife Assessment

This manuscript focuses on developing a structural model of how the multidomain ECM protein SVEP1 enables Angiopoietin (ANG) binding to the orphan receptor TIE1, resulting in downstream receptor phosphorylation and signaling. This is a potentially important study, however, it currently lacks key controls and is therefore incomplete. The data will be of interest to scientists working in vascular biology and RTK signaling.

eLife Assessment

Engineering of adeno-associated virus (AAV) replication proteins may provide new insights into Parvoviral replication. The authors created a useful collection of Rep protein variants with changes that alter the amino acid sequence, but these did not lead to clear improvements in how the virus worked. Instead, their screen showed that changes that do not alter the protein ("synonymous" mutations) and changes to the promoter were more common. As it stands the results are incomplete due to potential issues with the screening design. We encourage a more complete characterization, which may enhance the translational potential of the approach.

eLife assessment

This important study investigates the adaptability of prey capture by archerfish, which hunt insects by spitting at them and then rapidly turning to reach their landing point on the water surface. The results of elaborate behavioral experiments and measurements show that, even though the visuomotor behavior unfolds very rapidly (in less than 100 ms), it is not hardwired and can adapt to different simulated physics and different prey shapes. The data are convincing and should be of relevance to those interested in rapid decision making in general, beyond the archerfish model.

eLife Assessment

This manuscript reports a useful computational study of information encoding across the monkey prefrontal and pre-motor cortices during decision making. While many of the conclusions are supported with solid analyses, the evidence for the main interpretation of the results, the role of an information bottleneck across areas, is not complete. The results will be of interest to a systems and computational neuroscience audience.

eLife Assessment

This important work substantially advances our understanding of reactive oxygen species (ROS) as a regenerative signal during postnatal cerebellum repair by activating adaptive progenitor reprogramming. The evidence supporting the conclusions is compelling, with rigorous genomic assays and in vivo analyses. This work will be of broad interest to biologists working on stem cells, neurodevelopment and regenerative medicine.

eLife Assessment

This study presents a valuable observation of how deletion of a major repair protein in bacteria can facilitate the rise of mutations that confer resistance against a range of different antibiotics. The data presented are convincing, and the authors addressed the concerns raised by the reviewers in their resubmission, improving the strength of their findings.

eLife Assessment

The authors provide a valuable contribution by documenting the role of microglia in pruning the axon terminals of AgRP neurons. The analysis of microglial axonal pruning is solid; however, the analysis of the effects inhibiting microglia on subsequent food consumption is not fully complete.

eLife Assessment

By performing a chemical screen of an FDA-approved library of small molecules against a leucine-dependent Mtb strain, this work discovered that semapimod inhibits Mtb growth by impairing leucine import. The work is useful because it connects leucine uptake with the cell wall lipids in Mtb; however, it remains incomplete as the evidence supporting semapimod's ability to target leucine uptake needs more substantial proof. The work requires significant experimental evidence to identify leucine transporter(s) and determine how PDIM participates in leucine uptake.

eLife Assessment

This useful study shows a protective role of type 1 IFN during Mycobacterium tuberculosis infection. It shows that the type 1 IFN response in human skin TST inversely correlates with TB severity, suggesting its protective role. Considering that type I IFN is usually shown to be pro-pathogenic, the higher vulnerability of zebrafish larvae lacking stat2 to M marinum infection is a strong result. However, the conclusion that IFN-I is protective during mycobacterial infection remains indirect and incomplete; the study requires additional mechanistic insights and validation.

eLife Assessment

This study presents an alternative to conventional and UV-based tetramers, which are easy to use and reliable for the identification of antigen-specific CD8 T cells. The authors demonstrate that tetramers for HLA alleles A0301, A1101, B0702, and C0702 can be subjected to specific temperatures that facilitate peptide exchange, whilst maintaining structural integrity. Whilst the strength of the evidence is currently incomplete, further development and validation of this approach is likely to provide a useful alternative to generating reagents for examining T cell specificities.

eLife Assessment

This study presents an important finding linking the bacterial metabolite trimethylamine and its receptor to circadian rhythms and olfaction. The current evidence supporting the claims of the authors is convincing, although further data and improvements to the presentation would further increase the impact of these results. This work will be of broad interest to researchers interested in nutrition, microbial metabolism, circadian rhythms, and host-microbiome interactions.

eLife Assessment

Endothelial cell-specific loss of TGF-beta signaling in mice leads to CNS vascular defects, specifically impairing retinal development and promoting immune cell infiltration. The data are solid, showing that loss of TGF-beta signaling triggers vascular inflammation and attracts immune cells specific to CNS vasculature, but there are issues with the single-nucleus RNA sequencing of immune cells. These findings are valuable, highlighting TGF-beta's role in maintaining vascular-immune homeostasis and its therapeutic potential in neurovascular inflammatory diseases.

eLife Assessment

This important study provides converging results from complementary neuroimaging and behavioral experiments to identify human brain regions involved in representing regular geometric shapes. Geometric shape concepts are universally present across diverse human cultures and possibly essential for unique human capabilities such as numerical cognition and symbolic reasoning, and identifying the brain networks involved in geometric shape representation is of broad interest to researchers studying human visual perception, reasoning, and cognitive development. The provided experimental evidence regarding the presence of geometric shape regularity representation in dorsal parietal and prefrontal cortex is solid, but the claimed link with mathematical reasoning, the influence of experimental tasks, and the role of experience in driving geometric shape representation in both humans and artificial vision models require further elucidation.

eLife Assessment

This fundamental study combines in vitro reconstitution experiments and molecular dynamics simulations to elucidate how membrane lipids are transported from the outer to the inner membrane of mitochondria. The authors provide convincing evidence that a positive membrane curvature is critical for membrane lipid extraction. The work will be of broad interest to cell biologists and biochemists.

eLife Assessment

This is a very important study in which the authors have modified ChIP-seq and 4C-seq with a urea step, which drastically changes the pattern of chromatin interactions observed for SATB1, but not other proteins (including CTCF). The study highlights that the urea protocols provide a complementary view of protein-chromatin interactions for some proteins, which can uncover previously hidden, functionally significant layers of chromatin organization. If applied more widely, these protocols may significantly further our understanding of chromatin organization. The study's findings are supported by a wealth of controls, making the evidence compelling.

eLife Assessment

This useful modeling study shows how spatial representations, similar to those seen in experimental data, emerge in a recurrent neural network trained on a navigation task. The training required path integration and decodability but did not rely on grid cell inputs. The network modeling is solid, though the link to experimental data could be strengthened.

eLife Assessment

The study investigated the effects of the peptide galanin on brain Ca2+ activity in zebrafish, which provides a useful model organism for whole-brain imaging because of its transparency. They found that galanin has distinct effects on hyperactivity and expression of galanin changes after activity increases. The strength of evidence was incomplete particularly for some of the conclusions regarding the use of convulsants and relevance to epilepsy because of limitations to the methods and interpretations of results.

eLife Assessment

The authors investigated KLF Transcription Factor 16 (KLF16) as an inhibitor of osteogenic differentiation, which plays a critical role in bone development, metabolism and repair. The results of the study are valuable as they could help to facilitate future research on the regulation of osteogenesis in vitro and in vivo. However, the evidence overall is incomplete, as validation by knockout mouse models would help to strengthen the conclusions.

eLife Assessment

This useful study presents a virtual reality-based contextual fear conditioning paradigm for head-fixed mice. Solid evidence supports the claim that the reported methods provide a reliable paradigm for studying contextual fear conditioning in head-fixed mice. The approach provides a way to perform multiphoton imaging of neural circuits, and other techniques that are typically performed in head-fixed animals, during behaviors that have traditionally been studied in freely moving animals.

eLife Assessment

This valuable study by Guo and colleagues reports the inhibitory activity of caffeic acid phenethyl ester (CAPE) against TcdB, a key toxin produced by Clostridioides difficile. C. difficile infections are a major public health concern, and this manuscript provides interesting data on toxin inhibition by CAPE, a potentially promising therapeutic alternative for this disease. The strength of the evidence to support the conclusions is solid, with some concerns about the moderate effects on the mouse infection model and direct binding assays of CAPE to the toxin.

eLife Assessment

This manuscript provides an important biochemical analysis of p53 isoforms, highlighting their aggregation propensity, interaction with chaperones, and dominant-negative effects on p53 family members. The authors have substantially strengthened the original manuscript by incorporating new mass spectrometry data and clarifying isoform-specific oligomerization behavior. Although the use of high expression levels limits direct physiological interpretation, the work is carefully framed as an investigation of protein misfolding and stability. Overall, this study offers convincing insights into p53 isoform biophysics with broad implications for cancer biology.

eLife Assessment

This study presents an advance in efforts to use histone post-translational modification (PTM) data to model gene expression and to predict epigenetic editing activity. Such models are broadly useful to the research community, especially ones that can model and predict epigenetic editing activity, which is novel; additionally, the authors have nicely integrated datasets across cell types into their model. The work is mostly solid, but it would be strengthened by performing further comparisons to existing methods that predict gene expression from PTM data and from more comprehensive functional validation of model-predicted epigenome editing outcomes beyond dCas9-p300 based perturbations. This work will be of interest to the epigenetics and computational modeling communities.

eLife Assessment

This study, which includes additional experiments in response to the reviewer comments, presents valuable findings illustrating the role of PI3Kα in heterotopic ossification in FOP model mice. The methods, data, and analyses are solid and generally support the claims although as noted by one of the reviewers, there is no data demonstrating the effect of BYL79 on cell growth, and it remains unclear whether BYL79 also inhibits the Smad2/3 pathway. While this study provides new insights into the role of the PI3Kα pathway as a therapeutic target for FOP, questions about the mechanism of BYL79 still exist.

eLife Assessment

Using a unique cerebellar disruption approach in non-human primates, this study provides valuable new insight into how cerebellar inputs to the motor cortex contribute to reaching. The findings convincingly demonstrate that reaching movements following cerebellar disruption slow down because of both an acute deficit in producing muscle activity as well as a progressive decline in compensating for limb dynamics. This work will be of interest to neuroscientists and clinicians interested in cerebellar function and pathology.

eLife Assessment

By using sparse Cre-dependent deletion of GluN1 subunit, in vitro quadruple patch clamp recordings, and pharmacological interventions, the authors show that spike timing dependent plasticity at between L5 synapses in the mouse visual cortex is: (i) dependent on presynaptic NMDA receptors; (ii) mediated by non-ionotropic NMDA receptor signaling, and (iii) reliant on presynaptic JNK2/Syntaxin-1a interactions. These fundamental findings advance our understanding of the molecular mechanisms underlying spike time dependent plasticity. The data are compelling and are supported by the elegant application of sophisticated experimental approaches.

eLife Assessment

This study presents valuable findings that advance our understanding of mural cell dynamics and vascular pathology in a zebrafish model of cerebral small vessel disease. The authors provide compelling evidence that partial loss of foxf2 function leads to progressive, cell-intrinsic defects in pericytes and associated endothelial abnormalities across the lifespan, leveraging powerful in vivo imaging and genetic tools. The strength of evidence could be further improved by additional mechanistic insight and quantitative or lineage-tracing analyses to clarify how pericyte number and identity are affected in the mutant model.

eLife Assessment

This study identifies 53BP1 as an interaction partner of GMCL1 (a likely CUL3 substrate receptor). The study seeks to link this finding to regulation of the mitotic surveillance pathway and paclitaxel resistance in cancer. The evidence for these claims is currently inadequate; concerns include the use of cell lines that have been reported to lack the mitotic surveillance pathway, insufficient consideration of paclitaxel mechanisms of action, and an overinterpretation of correlative results.

eLife Assessment

This valuable study expands the inventory of polyadenylated RNAs cleaved by the double-stranded RNA endonuclease Rnt1 in budding yeast, using solid methodology based on high-throughput sequencing. Previous studies had anecdotally discovered mRNA substrates, and this global characterization is comprehensive with multiple complementary controls. However, the study would be stronger with a deeper investigation into the biological function of Rnt1, as well as experiments directly probing the interaction between Rnt1 and its putative substrates.

eLife Assessment

Complex traits are influenced by genes and the environment, but especially the latter is difficult to pin down. This important study uses C. elegans to demonstrate that non-genetic differences in gene expression, partly influenced by the environment, correlate with individual differences in two reproductive traits. This supports the use of gene expression data as a key intermediate for understanding complex traits. The clever study design makes for compelling evidence, which is further strengthened by experimental confirmation that identified differentially expressed genes indeed influence these traits.

eLife Assessment

This useful study presents the potentially interesting concept that LRRK2 regulates cellular BMP levels and their release via extracellular vesicles, with GCase activity further modulating this process in mutant LRRK2-expressing cells. However, the evidence supporting the conclusions remains incomplete, and certain statistical analyses are inadequate. This work would be of interest to cell biologists working on Parkinson's disease.

eLife Assessment

This fundamental study advances our understanding of the role that energy metabolism, specifically anaerobic glycolysis, plays during retinal development. Convincing in vitro genetic and pharmacological evidence demonstrates that glycolytic flux controls retinal progenitor cell proliferation rates and the timing of photoreceptor maturation. Interesting evidence suggests potential downstream roles for intracellular pH and Wnt/β-catenin signaling; however, more direct evidence is needed to show they are the key mechanisms through which glycolytic flux regulates retinogenesis in vivo. This work is expected to stimulate broad interest and possible future studies investigating the link between metabolism and development in other tissue systems.

[Editors’ note: Primary data for this manuscript are not available due to a corrupted hard drive that occurred during the course of peer review. However, preprocessed data are available.]

eLife Assessment

This landmark study describes the structure of the human RAD51 filament with a recombination intermediate called the displacement loop (D-loop). Using cryogenic structural, biochemical, and single-molecule analyses, the authors provide compelling evidence on how the RAD51 filament promotes strand exchange between single-stranded and double-stranded DNAs. The work will be of interest to the community of homologous recombination and DNA repair, as well as genome stability more generally.